Ortho-fluoro substituted compounds for the treatment of metabolic diseases

ABSTRACT

There is provided novel fluoro-substituted compounds capable of modulating the G-protein-coupled receptor GPR40, compositions comprising the compounds, and methods for their use for controlling insulin levels in vivo and for the treatment of conditions such as type II diabetes, hypertension, ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels.

This application is a National Stage Application of PCT/DK2012/050108,filed 3 Apr. 2012, which claims benefit of Serial No. PA 2011 00279,filed 8 Apr. 2011 in Denmark, and claims benefit of U.S. ProvisionalSer. No. 61/473,228, filed 8 Apr. 2011, and which applications areincorporated herein by reference. To the extent appropriate, a claim ofpriority is made to each of the above disclosed applications.

FIELD OF THE INVENTION

The present invention relates to novel 2-halo substituted compoundscapable of modulating the G-protein-coupled receptor GPR40, compositionscomprising the compounds, and methods for their use for controllinginsulin levels in vivo and for the treatment of conditions such as typeII diabetes, hypertension, ketoacidosis, obesity, glucose intolerance,and hypercholesterolemia and related disorders associated withabnormally high or low plasma lipoprotein, triglyceride or glucoselevels.

BACKGROUND OF THE INVENTION

The production of insulin is central to the regulation of carbohydrateand lipid metabolism. Insulin imbalances lead to conditions such as typeII diabetes mellitus, a serious metabolic disease that currentlyafflicts approximately 246 million people worldwide, and is expected toaffect 380 million by 2025. Insulin is secreted from pancreaticbeta-cells in response to elevated plasma glucose which is augmented bythe presence of fatty acids. The recent recognition of the function ofthe G-protein coupled receptor GPR40 in modulating insulin secretion hasprovided insight into regulation of carbohydrate and lipid metabolism invertebrates, and further provided targets for the development oftherapeutic agents for disorders such as obesity, diabetes,cardiovascular disease and dyslipidemia.

GPR40 is a member of the gene superfamily of G-protein coupled receptors(GPCRs) or 7-transmembrane receptors (7TM receptors). These receptorsare membrane proteins characterized as having seven transmembranedomains, and respond to a variety of molecules by activatingintra-cellular signalling pathways critical to a diversity ofphysiological functions.

At present there is no cure for diabetes, but the disease can often bemanaged satisfactory, and various treatments are used to ameliorate thedisease. For example, dietetic measures have been employed to balancethe relative amounts of proteins, fats, and carbohydrates in a patient.Diabetes education and awareness programmes have also been implementedin several countries. In addition, diabetic conditions of moderate orsevere intensity are treated by the administration of insulin. Also,prescription drugs such as thiazolinediones have been employed torejuvenate impaired insulin production in adult onset diabetics. Otherdrugs are used to modulate the effectiveness of insulin. In any case,treatment of either juvenile or adult onset diabetes, has achieved onlypartial success. This is due to most agents targeting either improvedbeta-cell function or reducing insulin resistance, with the effectattenuating as the disease progressively worsens. Thus patients requirethe use (often daily) of a combination of agents to control the disease.

Biguanides, such as metformin, became available for treatment of type 2diabetes in the late 1950s, and have been effective hypoglycaemic agentsever since (Vigneri and Goldfine (1987) Diabetes Care 10, 118-122).Little is known about the exact molecular mechanism of these agents. Asan insulin sensitizer, metformin acts predominantly on the liver, whereit suppresses glucose release (Goldfine (2001) Hospital Practice 36,26-36). Metformin has also been shown to inhibit the enzymatic activityof complex I of the respiratory chain and thereby impairs bothmitochondrial function and cell respiration, and in so doing decreasingthe ATP/ADP ratio which activates AMP-activated protein kinase (AMPK),causing catabolic responses on the short term and insulin sensitizationon the long term (Brunmair et al. (2004) Diabetes 53, 1052-1059;Tiikkainen et al. (2004) Diabetes 53, 2169-2176). This drug has beenproven effective in both monotherapy and in combination withsulfonylureas or insulin (Davidson and Peters (1997) American Journal ofMedicin 102, 99-110). Diabetes in the young is a global phenomenon thatis increasing in incidence. Some key transcription factors, importantfor beta-cell development, differentiation and function, are implicatedin diabetes in the young. Some of these are direct targets of currenttherapeutic agents. The cost of current diabetic drugs is very high andthe development of more affordable alternative therapies would be anadvantage. The global burden of type 2 diabetes is huge, and action isrequired to endure affordable diabetes treatment to improve the qualityof life of those individuals affected.

As a result of its adipogenic effect, insulin has the undesirable effectof promoting obesity in patients with type 2 diabetes. (Moller, D. E.(2001) Nature 414:821-827). Unfortunately, other anti-diabetic drugs,including metformin, which are currently being used to stimulate glucosetransport in patients with type 2 diabetes also possess adipogenicactivity. Thus while current drug therapy may provide reduction in bloodsugar, it often promotes obesity. Accordingly, new compositions andmethods for treating hyperglycemia are desirable. Compositions thatstimulate glucose uptake without generating concomitant adipogenic sideeffects and with no risk of causing excess insulin secretion andconcequential hypoglycaemia are especially desirable.

The seven-transmembrane receptor GPR40, or free fatty acid receptor 1(FFA₁/FFAR1), was recently found to be highly expressed on pancreaticbeta-cells, and activated by physiological concentrations of free fattyacids. Activation of GPR40 enhanced glucose-stimulated insulin secretion(GSIS), but did not affect insulin secretion at low glucoseconcentrations. The enhancement of GSIS by GPR40 has been confirmed invivo. Furthermore, two single nucleotide polymorphisms of GPR40significantly correlating to obesity and impaired insulin secretion,further validating the link between the receptor and the disease.

WO08030618A1 (BENZO-FUSED COMPOUNDS FOR USE IN TREATING METABOLICDISORDERS) discloses compositions for treating metabolic disorders suchas type II diabetes. This document specifically relates to compoundscapable of modulating GPR40.

WO05086661A2 (COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USEIN TREATING METABOLIC DISORDERS) describes alkynyl containing compoundscapable of modulating the G-protein-coupled receptor GPR40, compositionscomprising the compounds, and methods for their use for controllinginsulin levels in viva and for the treatment of conditions such as typeII diabetes.

WO08001931A2 (FUSED CYCLIC COMPOUNDS) describes novel fused cycliccompounds having a GPR40 receptor function modulating action, and whichare useful as insulin secretagogues or agents for the prophylaxis ortreatment of diabetes and the like.

US20080021069A1 (Receptor Function Regulating Agent) also relates to aGPR40 receptor function regulator comprising a fused imidazole compound.According to the specification the GPR40 receptor function regulator isuseful as an agent for the prophylaxis or treatment of obesity,hyperinsulinemia, type 2 diabetes and the like.

WO08054675A2 (ANTIDIABETIC BICYCLIC COMPOUNDS) focuses on a new class ofGPR40 agonists. The compounds are useful in the treatment of diseasesthat are modulated by GPR40 agonists, including type 2 diabetes andhyperglycemia that may be associated with type 2 diabetes orpre-diabetic insulin resistance.

WO05051890A1 (AMINOPHENYLCYCLOPROPYL CARBOXYLIC ACIDS AND DERIVATIVES ASAGONISTS TO GPR40) discloses novel therapeutic compounds for use asGPR40 agonists.

WO05087710A1 discloses compounds with GPR40 receptor agonistic activity.They can be a medicine which is safe and useful as apreventive/therapeutic agent for pathological states or diseases inwhich a GPR40 receptor participates, such as diabetes.

WO05063729A1 discloses compounds having a GPR40 receptor functionmodulating action, which can be used as an insulin secretagogue, anagent for the prophylaxis or treatment of diabetes and the like.

Winzell and Ahrén (G-protein-coupled receptors and isletfunction—Implications for treatment of type 2 diabetes—Pharmacology &Therapeutics 116 (2007) 437-448) confirm that many efforts have beenmade to produce small molecule GPR40 receptor agonists and antagoniststo investigate their potential as drugs for type 2 diabetes. It ismentioned that in clonal β cells, insulin secretion could be potentiatedby addition of a GPR40 agonist, suggesting that acute activation ofGPR40 may be useful to stimulate insulin secretion. However, since themouse model with transgenic over-expression of GPR40 exhibited impairedβ-cell function and type 2 diabetes chronic activation of the receptormay cause deleterious effects. Therefore, the authors suggest that aGPR40 antagonist may be a more efficient concept because patients withtype 2 diabetes usually have elevated circulating free fatty acids.

Briscoe et al (Pharmacological regulation of insulin secretion in MIN6cells through the fatty acid receptor GPR40: identification of agonistand antagonist small molecules—British Journal of Pharmacology (2006)148, 619-628) disclose the pharmacology of a novel small-moleculeagonist of GPR40 together with a selective antagonist of GPR40. Usingthese compounds, the authors verify that the potentiation of insulinsecretion by fatty acids appears to be mediated at least partiallythrough GPR40, and that GPR40 agonists can function as glucose-sensitivesecretagogues in vitro.

Gamido et al. (Synthesis and activity of small molecule GPR40agonists—Bioorganic & Medicinal Chemistry Letters (2006) 16, 1840-1845)and McKeown et al (Solid phase synthesis and SAR of small moleculeagonists for the GPR40 receptor—Bioorganic & Medicinal Chemistry Letters(2007) 17, 1584-1589) focus on small molecule GPR40 receptor agonistsand antagonists to investigate their potential as drugs for type 2diabetes. The data gathered in the present work suggest that a smallmolecule GPR40 ligand could help regulate insulin secretion and as suchpresent GPR40 as a potential target for Type II Diabetes.

Tan et al. (Selective small-molecule agonists of G protein-coupledreceptor 40 promote glucose-dependent insulin secretion and reduce bloodglucose in mice—Diabetes (2008) 57, 2211-2219) studied three newselective GPR40 agonists in wild-type and GPR40 knock-out mice in acuteand chronic studies, and concluded that GPR40 does not mediate thechronic toxic effect of free fatty acids on pancreatic islet function,but potentiate GSIS after both acute and chronic administration, and maytherefore be of potential benefit for control of type 2 diabetes also inhumans.

WO 2009/034388 (COMPOUNDS FOR THE TREATMENT OF METABOLIC DISORDERS)discloses therapeutic compounds which have dual activity as agonists ofGPR119 and inhibitors of DPP-IV and are useful for the treatment ofmetabolic disorders including type II diabetes. In Preparation 124 onpage 63 of this international application there is disclosed anintermediate, namely:

which is covered by the general formula of the present invention. Hence,this intermediate, which has not been ascribed any activity related toGPR119 and/or DPP-IV, is herewith excluded from the scope of the presentinvention.

Hereinafter, none of the documents disclose the compounds of the presentinvention.

SUMMARY OF THE INVENTION

Provided herein are compounds, pharmaceutical compositions and methodsuseful for treating or preventing a condition or disorder such as typeII diabetes, obesity, hyperglycemia, glucose intolerance, insulinresistance, hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema. Ithas surprisingly been found that ortho-fluoro substituted compounds ofthe relevant class possess superior antidiabetic potential compared tocorresponding meta- and para-substituted analogs.

In one aspect the present invention provides a compound of the formula(I)

or a salt thereofwhereinAr is an optionally substituted monocyclic or fused aromatic orheteroaromatic ring system;n is an integer of 0-1;X is —C(R⁴R⁵)—, —N(R⁴)—, —O—, or —S(O)_(m)—;m is an integer of 0-2;R¹, R⁴, and R⁶ are independently selected from the group consisting ofhydrogen, (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl,(C₁-C₁₀)alkylene, (C₁-C₁₀)alkoxy, hydroxy, (C₂-C₁₀)dialkylamino,(C₁-C₁₀)alkylthio, (C₂-C₁₀)heteroalkyl, (C₂-C₁₀)heteroalkylene,(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)heterocycloalkyl, (C₃-C₁₀)cycloalkylene,(C₃-C₁₀)heterocycloalkylene, halo, nitrile, (C₁-C₁₀)alkylsulfenyl,(C₁-C₁₀)alkylsulfinyl, (C₁-C₁₀)alkylsulfonyl, (C₁-C₁₀)haloalkyl,(C₁-C₁₀)perhaloalkyl, (C₂-C₁₀)-alkenyloxy, (C₃-C₁₀)-alkynyloxy, aryloxy,arylalkyloxy, heteroaryloxy, heteroarylalkyloxy,(C₁-C₆)alkyloxy-(C₁-C₄)alkyl optionally substituted aryl, optionallysubstituted heteroaryl, and optionally substituted arylalkyl;R² is selected from the group consisting of (C₁-C₁₀)alkyl,(C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, (C₁-C₁₀)alkylene, (C₂-C₁₀)heteroalkyl,(C₂-C₁₀)heteroalkenyl, (C₂-C₁₀)heteroalkylene, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)cycloalkenyl, (C₃-C₁₀)cycloalkylene, (C₃-C₁₀)heterocycloalkyl,(C₃-C₁₀)heterocycloalkenyl, (C₃-C₁₀)heterocycloalkylene,(C₁-C₁₀)haloalkyl, (C₁-C₁₀)haloalkenyl, (C₁-C₁₀)haloalkylene,(C₁-C₁₀)perhaloalkyl, (C₁-C₁₀)perhaloalkenyl, (C₁-C₁₀)perhaloalkylene,and optionally substituted arylalkyl;Ar and R² may be further substituted by R⁶;R³ is selected from hydrogen and halogen;R⁵ is selected from hydrogen and optionally substituted (C₁-C₃)alkyl;- - - define that R¹ and R⁴, when not selected from halo, may optionallybe connected to the benzene ring in ortho position relative to X, to R³,to X or to each other by a covalent bond, —O—, or —S(O)_(n)—.

Preferably X is —C(R⁴R⁵)—. It is also preferred that R¹, R⁴ and R⁵ areindependently selected from hydrogen and (C₁-C₃)alkyl. In anotherpreferred embodiment of the invention R¹ is hydrogen. Compounds, whereinR⁴ and R⁵ are hydrogen, are also preferred.

Concerning Ar this is preferably selected from the group consisting ofan optionally substituted benzene, pyridine, thiophene, thiazole, furan,oxazole, pyrrole, pyrrazole, pyrimidine, triazole, tetrazole,naphthalene, quinoline, and indole. In a particularly preferredembodiment Ar is benzene or pyridine.

Preferably n is 1 and R² is substituted in the ortho or meta positionrelative to the alkyne. R² is selected from (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)heteroalkyl, (C₂-C₆)heteroalkenyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkenyl. In a particularly preferredembodiment R² is selected from hydrogen and (C₁-C₆)alkyl. Preferably R²is (C₁-C₃)alkyl substituted by nitrile.

In another preferred embodiment of the present invention n is 0 and R²is selected from (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)heteroalkyl,(C₂-C₁₀)heteroalkenyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkenyl,(C₅-C₁₀)bicycloalkyl, (C₅-C₁₀)heterobicycloalkyl,(C₃-C₁₀)heterocycloalkenyl. More preferably n is 0 and R² is(C₄-C₆)cycloalken-1-yl substituted by 1-3 R⁶ groups.

Due to prior art the following compound is excluded from protection:

-   (S)-2-tert-Butoxycarbonylamino-3-(4-{(R)-4-[1-(5-chloropyrimidin-2-yl)-piperidin-4-yl]pent-1-ynyl}-2-fluorophenyl)propionic    acid

In some embodiments, a compound of the present invention comprise astereomerically pure S-enantiomer. In other embodiments, the compoundcomprises a stereomerically pure R-enantiomer. In yet other embodiments,the compound comprises a mixture of S- and R-enantiomers.

In another aspect, the invention provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier, diluent, or excipient,and a compound of any of the embodiments of the invention. According toa preferred embodiment there is provided compounds of the presentinvention for use as medicaments.

In another aspect, the invention provides methods for treating orpreventing a disease or condition selected from the group consisting oftype II diabetes, obesity, hyperglycemia, glucose intolerance, insulinresistance, hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, hypertension,cancer, and edema. Such methods include administering to a subject inneed thereof, a therapeutically effective amount of a compound of any ofthe embodiments. In some such embodiments, the disease or condition istype II diabetes.

In some embodiments, a compound of any of the embodiments isadministered with combination with a second therapeutic agent. In somesuch embodiments, the second therapeutic agent is metformin or is athiazolidinedione. The second therapeutic agent may be administeredbefore, during, or after administration of the compound of any of theembodiments.

In another aspect, the invention provides methods for treating orpreventing a disease or condition responsive to the modulation of GPR40.Such methods include administering to a subject in need thereof, atherapeutically effective amount of a compound of any of theembodiments.

In another aspect, the invention provides methods for treating orpreventing a disease or condition mediated, regulated, or influenced bypancreatic beta-cells. Such methods include administering to a subjectin need thereof, a therapeutically effective amount of a compound of anyof the embodiments.

In another aspect, the invention provides methods for modulating GPR40function in a cell. Such methods include contacting a cell with acompound of formula any of the embodiments.

In another aspect, the invention provides methods for modulating GPR40function. Such methods include contacting GPR40 with a compound of anyof the embodiments.

In another aspect, the invention provides methods for modulatingcirculating insulin concentration in a subject. Such methods includeadministering a compound of any of the embodiments to the subject. Insome such embodiments, the circulating insulin concentration isincreased in the subject after administration whereas in other suchembodiments, the circulating insulin concentration is decreased in thesubject after administration.

In another aspect, the invention provides the use of a compound of anyof the embodiments for treating a disease or condition or for preparinga medicament for treating a disease or condition where the disease orcondition is selected from the group consisting of type II diabetes,obesity, hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.In some such embodiments, the disease or condition is type II diabetes.The compounds of the invention may also be used to prepare medicamentsthat include a second therapeutic agent such as metformin or athiazolidinedione.

In another aspect, the invention provides the use of a compound of anyof the embodiments for modulating GPR40 or for use in the preparation ofa medicament for modulating GPR40.

In another aspect, the invention provides a therapeutic composition thatincludes a compound of any of the embodiments and a second therapeuticagent such as those described herein, for example, metformin or athiazolidinedione, as a combined preparation for simultaneous, separate,or sequential use in the treatment of a disease or condition mediated byGPR40. In some such embodiments, the disease or condition is type IIdiabetes. In some embodiments, the compound of any of the embodimentsand the second therapeutic agent are provided as a single composition,whereas in other embodiments they are provided separately as parts of akit.

DETAILED DESCRIPTION OF THE INVENTION

The terms “treat”, “treating” and “treatment”, as used herein, are meantto include alleviating or abrogating a condition or disease and/or itsattendant symptoms. The terms “prevent”, “preventing” and “prevention”,as used herein, refer to a method of delaying or precluding the onset ofa condition or disease and/or its attendant symptoms, barring a subjectfrom acquiring a condition or disease, or reducing a subject's risk ofacquiring a condition or disease.

The term “therapeutically effective amount” refers to that amount of thecompound that will elicit the biological or medical response of atissue, system, or subject that is being sought. The term“therapeutically effective amount” includes that amount of a compoundthat, when administered, is sufficient to prevent development of, oralleviate to some extent, one or more of the symptoms of the conditionor disorder being treated in a subject. The therapeutically effectiveamount in a subject will vary depending on the compound, the disease andits severity, and the age, weight, etc., of the subject to be treated.

The term “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function or activity of GPR40either directly or indirectly. Inhibitors are compounds that, forexample, bind to, partially or totally block stimulation, decrease,prevent, delay activation, inactivate, desensitize, or down regulatesignal transduction, such as, for instance, antagonists. Activators arecompounds that, for example, bind to, stimulate, increase, activate,facilitate, enhance activation, sensitize or up regulate signaltransduction, such as agonists for instance. Modulation may occur invitro or in vivo.

As used herein, the phrases “GPR40-mediated condition or disorder”,“disease or condition mediated by GPR40”, and the like refer to acondition or disorder characterized by inappropriate, for example, lessthan or greater than normal, GPR40 activity. A GPR40-mediated conditionor disorder may be completely or partially mediated by inappropriateGPR40 activity.

However, a GPR40-mediated condition or disorder is one in whichmodulation of GPR40 results in some effect on the underlying conditionor disease (e.g., a GPR40 modulator results in some improvement inpatient well-being in at least some patients). Exemplary GPR40-mediatedconditions and disorders include cancer and metabolic disorders, e.g.,diabetes, type II diabetes, obesity, hyperglycemia, glucose intolerance,insulin resistance, hyperinsulinemia, hypercholesterolemia,hypertension, hyperlipoproteinemia, hyperlipidemia,hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia,thrombotic disorders, metabolic syndrome, syndrome X and relateddisorders, e.g., cardiovascular disease, atherosclerosis, kidneydisease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, and edema.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which is fully saturated,having the number of carbon atoms designated (e.g., C1-C10 means one toten carbons). Examples of alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, and homologs andisomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike.

The term “alkenyl”, by itself or as part of another substituent, means astraight or branched chain, or cyclic hydrocarbon radical, orcombination thereof, which may be mono- or polyunsaturated, having thenumber of carbon atoms designated (i.e., C₂-C₈ means two to eightcarbons) and one or more double bonds. Examples of alkenyl groupsinclude vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), and higher homologs and isomersthereof.

The term “alkynyl”, by itself or as part of another substituent, means astraight or branched chain hydrocarbon radical, or combination thereof,which may be mono- or polyunsaturated, having the number of carbon atomsdesignated (i.e., C₂-C₈ means two to eight carbons) and one or moretriple bonds. Examples of alkynyl groups include ethynyl, 1- and3-propynyl, 3-butynyl, and higher homologs and isomers thereof.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from alkyl, as exemplified by —CH₂CH₂CH₂CH₂—.The two valences may be on any carbon atom of the chain, including onthe same carbon, resulting in an alkyl connected by a double bond.Typically, an alkyl (or alkylene) group will have from 1 to 24 carbonatoms, with those groups having 12 or fewer carbon atoms being preferredin the present invention. A “lower alkyl” or “lower alkylene” is ashorter chain alkyl or alkylene group, generally having eight or fewercarbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Similarly, the term dialkylaminorefers to an amino group having two attached alkyl groups. The alkylgroups of a dialkylamino may be the same or different.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting ofcarbon atoms and from one to three heteroatoms selected from the groupconsisting of O, N, and S, and wherein the nitrogen and sulfur atoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N, and S may be placed at any positionof the heteroalkyl group. Examples include —CH₂CH₂OCH₃, —CH₂CH₂NHCH₃,—CH₂CH₂N(CH₃)CH₃, —CH₂SCH₂CH₃, —CH₂CH₂S(O)CH₃, —CH₂CH₂S(O)₂CH₃, and—CH₂CH═N—OCH₃. Up to two heteroatoms may be consecutive, such as, forexample, —CH₂NH—OCH₃. When a prefix such as (C₂-C₈) is used to refer toa heteroalkyl group, the number of carbons (2 to 8, in this example) ismeant to include the heteroatoms as well. For example, a C₂-heteroalkylgroup is meant to include, for example, —CH₂OH (one carbon atom and oneheteroatom replacing a carbon atom) and —CH₂SH.

To further illustrate the definition of a heteroalkyl group, where theheteroatom is oxygen, a heteroalkyl group is an, oxyalkyl group. Forinstance, (C₂-C₈)oxyalkyl is meant to include, for example —CH₂O—CH₃ (aC₂-oxyalkyl group with two carbon atoms and one oxygen replacing acarbon atom), —CH₂CH₂CH₂CH₂OH, and the like.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from heteroalkyl, as exemplified by—CH₂CH₂SCH₂CH₂— and —CH₂SCH₂—CH₂NHCH₂—. For heteroalkylene groups,heteroatoms can also occupy either or both of the chain termini (e.g.,alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and thelike). Still further, for alkylene and heteroalkylene linking groups, noorientation of the linking group is implied. Heteroalkylene groups suchas oxymethyl groups (—CH₂O—) may be substituted or unsubstituted. Insome embodiments, heteroalkylene groups may be substituted with an alkylgroup. For example, the carbon atom of an oxymethylene group may besubstituted with a methyl group in a group of formula —CH(CH₃)O—.

The terms “cycloalkyl” and “heterocycloalkyl” by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl” respectively. Thus, the terms“cycloalkyl” and “heterocycloalkyl” are meant to be included in theterms “alkyl” and “heteroalkyl,” respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, 4,5-dihydroisoxazol-3-yl, and the like.The term “heterocycloalkyl” includes fully saturated compounds such aspiperidine and compounds with partial saturation that are not aromatic.Examples of such groups include, but are not limited to, an imidazole,oxazole, or isoxazole which has been partially hydrogenated so that itonly contains one double bond.

The term “cycloalkylene” and “heterocycloalkylene,” by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkylene” and “heteroalkylene,” respectively. Thus, theterms “cycloalkylene” and “heterocycloalkylene” are meant to be includedin the terms “alkylene” and “heteroalkylene,” respectively.Additionally, for heterocycloalkylene, one or more heteroatoms canoccupy positions at which the heterocycle is attached to the remainderof the molecule. Typically, a cycloalkylene or heterocycloalkylene willhave from 3 to 9 atoms forming the ring, more typically, 4 to 7 atomsforming the ring, and even more typically, 5 or 6 atoms will form thecycloalkylene or heterocycloalkylene ring.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl”, aremeant to include alkyl substituted with halogen atoms which can be thesame or different, in a number ranging from one to (2 m+1), where m isthe total number of carbon atoms in the alkyl group. For example, theterm “halo(C₁-C₄)alkyl” is meant to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

Thus, the term “haloalkyl” includes monohaloalkyl (alkyl substitutedwith one halogen atom) and polyhaloalkyl (alkyl substituted with halogenatoms in a number ranging from two to (2 m+1) halogen atoms). The term“perhaloalkyl” means, unless otherwise stated, alkyl substituted with (2m+1) halogen atoms, where m is the total number of carbon atoms in thealkyl group. For example, the term “perhalo(C1-C4)alkyl”, is meant toinclude trifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon ring. The term “heteroaryl” refers toaryl groups (or rings) that contain from one to four heteroatomsselected from the group consisting of N, O and S, wherein the nitrogenand sulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl and 4-pyridazinyl.

The term “fused aryl” means, unless otherwise stated, an aryl which isfused with another cyclic aromatic or non-aromatic ring. The term “fusedheteroaryl” means, unless otherwise stated, a heteroaryl which is fusedwith another cyclic aromatic or non-aromatic ring. Examples of fusedaryl and fused heteroaryl groups include 1-naphthyl, 2-naphthyl,4-biphenyl, dibenzofuryl, 5-benzothiazolyl, 2-benzoxazolyl,5-benzoxazolyl, benzooxadiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1H-indazolyl, carbazolyl, carbolinyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 6-quinolyl, 7-quinolyl, and 8-quinolyl.

Preferably, the term “aryl” refers to a phenyl group which isunsubstituted or substituted. Preferably, the term “heteroaryl” refersto a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, oxadiazolyl,isoxazolyl, thiazolyl, furyl, thienyl (thiophenyl), pyridyl, orpyrimidyl which is substituted or unsubstituted. Preferably, the term“fused aryl refers to naphthyl, indanyl, indenyl, or quinolyl.Preferably, the term “fused heteroaryl” refers to quinolyl,benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl,triazolyl, tetrazolyl, or quinoxalinyl group which is unsubstituted orsubstituted.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) is meant to include both substituted and unsubstitutedforms of the indicated radical, unless otherwise indicated. Preferredsubstituents for each type of radical are provided below.

The term “substituent”, which may be present on alkyl or heteroalkylradicals, as well as those groups referred to as alkylene, alkenyl,heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl,cycloalkenyl and heterocycloalkenyl, or on other groups indicated as“optionally substituted”, can be a variety of groups selected from:—OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NRR″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, and —NO₂, in a number ranging from zero to three, withthose groups having zero, one or two substituents being particularlypreferred. Other suitable substituents include aryl and heteroarylgroups. R′, R″ and R′″ each independently refer to hydrogen,unsubstituted (C₁-C₆)alkyl and (C₂-C₆)heteroalkyl, unsubstituted aryl,aryl substituted with one to three halogens, unsubstituted(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy or (C₁-C₄)-thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6- or 7-membered ring. For example, —NR′R″is meant to include 1-pyrrolidinyl and 4-morpholinyl.

Typically, an alkyl or heteroalkyl group will have from zero to threesubstituents, with those groups having two or fewer substituents beingpreferred in the present invention. More preferably, an alkyl orheteroalkyl radical will be unsubstituted or monosubstituted. Mostpreferably, an alkyl or heteroalkyl radical will be unsubstituted. Fromthe above discussion of substituents, one of skill in the art willunderstand that the term “alkyl” is meant to include groups such astrihaloalkyl (e.g., —CF₃ and —CH₂CF₃).

Preferred substituents for the alkyl and heteroalkyl radicals areselected from: —OR′, ═O, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′SO₂NR″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl and —NO₂, where R′ and R″ are as defined above. Furtherpreferred substituents are selected from: —OR′, ═O, —NR′R″, halogen,—OC(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′CO₂R″,—NR′—SO₂NR″R′″, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand are selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN,—NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, (C₁-C₄)alkyl and heteroalkyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl,(unsubstituted aryl)oxy-(C₁-C₄)alkyl, —C₂-C₅)alkynyl, and—(C₂-C₅)alkenyl.

As used herein, the term “benzo-fused cycloalkane ring” is meant toinclude bicyclic structures in which benzene is fused with a cycloalkane(or cycloheteroalkane).

As used herein, the term “heterobenzo-fused (C₅-C₈)cycloalkane ring” hasthe same meaning as “benzo-fused (C₅-C₈)cycloalkane ring” except thebenzene of the benzo-fused (C₅-C₈)cycloalkane ring is replaced with asix-membered heteroaryl ring comprising 1 or 2 nitrogen (N) atoms. The(C₅-C₈)cycloalkane of benzo-fused (C₅-C₈)cycloalkane rings andheterobenzo-fused (C₅-C₈)cycloalkane ring may include only carbon atoms,but may also include one or more heteroatoms. Such heteroatoms typicallyare selected from O, N, or S.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

The term “pharmaceutically acceptable salt” is meant to include a saltof the active compound which is prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on the compounddescribed herein. When a compound of the invention contains relativelyacidic functionalities, a base addition salt can be obtained bycontacting the neutral form of such compound with a sufficient amount ofthe desired base, either neat or in a suitable inert solvent. Examplesof pharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, or magnesium salt, or asimilar salt. When a compound of the invention contains relatively basicfunctionalities, an acid addition salt can be obtained by contacting theneutral form of such compound with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, or phosphorousacids and the like, as well as the salts derived from relativelynontoxic organic acids like acetic, propionic, isobutyric, maleic,malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic,benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, andthe like. Also included are salts of amino acids such as arginine andthe like, and salts of organic acids like glucuronic or galacturonicacids and the like (see, for example, Berge et al. (1977) J. Pharm. Sci.66:1-19). Certain specific compounds of the invention contain both basicand acidic functionalities that allow the compounds to be converted intoeither base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the invention.

In addition to salt forms, the invention provides compounds which are ina prodrug form. Prodrugs of the compounds described herein are thosecompounds that readily undergo chemical changes under physiologicalconditions to provide the compounds of the invention. Additionally,prodrugs can be converted to the compounds of the invention by chemicalor biochemical methods in an ex vivo environment. For example, prodrugscan be slowly converted to the compounds of the invention when placed ina transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent drug is not.

The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound of the invention which is administered asan ester (the “prodrug”), but then is metabolically hydrolyzed to thecarboxylic acid, the active entity. Additional examples include peptidylderivatives of a compound.

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a compound that issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure compound having one chiral center will besubstantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, more preferably greater than about90% by weight of one stereoisomer of the compound and less than about10% by weight of the other stereoisomers of the compound, even morepreferably greater than about 95% by weight of one stereoisomer of thecompound and less than about 5% by weight of the other stereoisomers ofthe compound, and most preferably greater than about 97% by weight ofone stereoisomer of the compound and less than about 3% by weight of theother stereoisomers of the compound. If the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it. A bonddrawn with a wavy line indicates that both stereoisomers areencompassed.

Various compounds of the invention contain one or more chiral centers,and can exist as racemic mixtures of enantiomers, mixtures ofdiastereomers or enantiomerically or optically pure compounds. Thisinvention encompasses the use of stereomerically pure forms of suchcompounds, as well as the use of mixtures of those forms. For example,mixtures comprising equal or unequal amounts of the enantiomers of aparticular compound of the invention may be used in methods andcompositions of the invention. These isomers may be asymmetricallysynthesized or resolved using standard techniques such as chiral columnsor chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers,Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen,S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables ofResolving Agents and Optical Resolutions p. 268 (EX. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind., 1972).

In one aspect, a class of compounds that modulates GPR40 is describedherein. Depending on the biological environment (e.g., cell type,pathological condition of the subject, etc.), these compounds canmodulate, e.g., activate or inhibit, the actions of GPR40. By modulatingGPR40, the compounds find use as therapeutic agents capable ofregulating insulin levels in a subject.

The compounds find use as therapeutic agents for modulating diseases andconditions responsive to modulation of GPR40 and/or mediated by GPR40and/or mediated by pancreatic beta-cells. As noted above, examples ofsuch diseases and conditions include diabetes, obesity, hyperglycemia,glucose intolerance, insulin resistance, cancer, hyperinsulinemia,hypercholesterolemia, hypertension, hyperlipoproteinemia,hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis,hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, nephropathy, thrombotic disorders,diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia andedema.

Additionally, the compounds are useful for the treatment and/orprevention of complications of these diseases and disorders (e.g., typeII diabetes, sexual dysfunction, dyspepsia and so forth).

While the compounds of the invention are believed to exert their effectsby interacting with GPR40, the mechanism of action by which thecompounds act is not a limiting embodiment of the invention.

Compounds contemplated by the invention include, but are not limited to,the exemplary compounds provided herein.

In another aspect, the invention provides pharmaceutical compositionssuitable for pharmaceutical use comprising one or more compounds of theinvention and a pharmaceutically acceptable carrier, excipient, ordiluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients (and in the specified amounts, ifindicated), as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

By “pharmaceutically acceptable” it is meant that the carrier,excipient, or diluent is compatible with the other ingredients of theformulation and is not deleterious to the recipient thereof.

Composition formulation may improve one or more pharmacokineticproperties (e.g., oral bioavailability, membrane permeability) of acompound of the invention (herein referred to as the active ingredient).

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art. All methodsinclude the step of bringing the active ingredient into association withthe carrier which constitutes one or more accessory ingredients. Ingeneral, the pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition, the active object compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with other non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid, or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,256,108,4,160,452, and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol.

Sweetening agents such as those set forth above, and flavoring agentsmay be added to provide a palatable oral preparation. These compositionsmay be preserved by the addition of an anti-oxidant such as ascorbicacid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

The pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include, for example, cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions, or suspensions,etc., containing the compounds of the invention are employed. As usedherein, topical application is also meant to include the use ofmouthwashes and gargles.

The pharmaceutical compositions and methods of the invention may furthercomprise other therapeutically active compounds, as noted herein, usefulin the treatment of type II diabetes, obesity, hyperglycemia, glucoseintolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia,hypertension, hyperlipoproteinemia, hyperlipidemia,hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X,cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis,thrombotic disorders, nephropathy, diabetic neuropathy, diabeticretinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia,cancer and edema.

In another aspect, the invention provides methods of treating orpreventing a disease or condition selected from the group consisting oftype II diabetes, obesity, hyperglycemia, glucose intolerance, insulinresistance, hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound or composition of the invention.

In one embodiment, the disease or condition is type II diabetes.

In another aspect, the present invention provides a method for treatinga disease or condition responsive to the modulation of GPR40 comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound or composition of the invention.

In some embodiments, the disease or condition is selected from the groupconsisting of type II diabetes, obesity, hyperglycemia, glucoseintolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia,hypertension, hyperlipoproteinemia, hyperlipidemia,hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X,cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis,thrombotic disorders, nephropathy, diabetic neuropathy, diabeticretinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia,cancer and edema.

In certain embodiments, a cell to be contacted can be made to express oroverexpress GPR40, for example, by expressing GPR40 from heterologousnucleic acid introduced into the cell or, as another example, byupregulating the expression of GPR40 from nucleic acid endogenous to thecell.

Depending on the disease to be treated and the subject's condition, thecompounds of the invention may be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal,local) routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration.

The invention also contemplates administration of the compounds of theinvention in a depot formulation, in which the active ingredient isreleased over a defined time period.

In the treatment or prevention of type II diabetes, obesity,hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema orother conditions or disorders associated with GPR40, an appropriatedosage level will generally be about 0.001 to 100 mg per kg patient bodyweight per day which can be administered in single or multiple doses.Preferably, the dosage level will be about 0.01 to about 25 mg/kg perday; more preferably about 0.05 to about 10 mg/kg per day. A suitabledosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range, thedosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of the invention can be combined or used in combinationwith other agents useful in the treatment, prevention, suppression oramelioration of the diseases or conditions for which compounds of theinvention are useful, including type II diabetes, obesity,hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.Such other agents, or drugs, may be administered, by a route and in anamount commonly used therefore, simultaneously or sequentially with acompound of the invention. When a compound of the invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe invention is preferred. Accordingly, the pharmaceutical compositionsof the invention include those that also contain one or more otheractive ingredients or therapeutic agents, in addition to a compound ofthe invention.

The compounds of the invention may be used in combination with a secondtherapeutic agent such as those described herein. Thus, in someembodiments, therapeutic compositions are provided that include acompound of the invention and a second therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of a subject with a disease or condition mediated by GPR40. insome embodiments, therapeutic compositions are provided that include acompound of the invention and a second therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in theprophylactic treatment of a subject at risk for a disease or conditionmediated by GPR40. In some such embodiments, the components are providedas a single composition. In other embodiments, the compound and thesecond therapeutic agent are provided separately as parts of a kit.

Examples of other therapeutic agents that may be combined with acompound of the invention, either administered separately or in the samepharmaceutical compositions, include, but are not limited to: (a)cholesterol lowering agents such as HMG-CoA reductase inhibitors (e.g.,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin andother statins), bile acid sequestrants (e.g., cholestyramine andcolestipol), vitamin B₃ (also known as nicotinic acid, or niacin),vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), fibric acidderivatives (e.g., gemfibrozil, clofibrate, fenofibrate andbenzafibrate), probucol, nitroglycerin, and inhibitors of cholesterolabsorption (e.g., beta-sitosterol and acylCoA-cholesterolacyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthaseinhibitors, squalene epoxidase inhibitors and squalene synthetaseinhibitors; (b) antithrombotic agents, such as thrombolytic agents(e.g., streptokinase, alteplase, anistreplase and reteplase), heparin,hirudin and warfarin derivatives, beta-blockers (e.g., atenolol),beta-adrenergic agonists (e.g., isoproterenol), ACE inhibitors andvasodilators (e.g., sodium nitroprusside, nicardipine hydrochloride,nitroglycerin and enaloprilat); and (c) anti-diabetic agents such asinsulin and insulin mimetics, sulfonylureas (e.g., glyburide,meglinatide), biguanides, e.g., metformin (GLUCOPHAGE®), glucosidaseinhibitors (acarbose), insulin sensitizers, e.g., thiazolidinonecompounds, rosiglitazone (Avandia), troglitazone (Rezulin), ciglitazone,pioglitazone (ACTOS®) and englitazone, DPP-IV inhibitors, e.g.,vildagliptin (Galvus®), sitagliptin (Januvia), and GLP-I analogs, e.g.exenatide (Byetta). In some embodiments, a compound of the invention maybe administered along with a DPP-IV inhibitor or a GLP-I analog.

The weight ratio of the compound of the invention to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used.Combinations of a compound of the invention and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

In another aspect, the present invention provides a method formodulating circulating insulin concentration in a subject, comprisingadministering a compound or composition of the invention.

EXAMPLES General Procedure I Sonogashira Coupling

A schlenk flask charged with Na₂PdCl₄ (1 mol %),2-(di-tert-butylphosphino)-N-phenylindole (PIntB, 2 mol %), CuI (2 mol%), aryl halide (1 equiv), H₂O (0.2 mL/mmol) and TMEDA (1.8 mL/mmol) wasevacuated and backfilled with argon three times, then heated to 70° C.The alkyne (1.1-2 equiv) was added and the reaction heated to 80° C.After consumption of the starting material monitored by HPLC, thereaction mixture was cooled to rt, added water and extracted with EtOAc(×3). The combined extracts were washed with brine, dried over MgSO₄,and concentrated, and the residue was purified by flash chromatography.

General Procedure II Ester Hydrolysis

A solution of acetylene methyl propanoate (1 equiv) in 1,4-dioxane/THF(4 mL) was added a solution of LiOH xH₂O (2-3 equiv) in H₂O (2 mL). Thereaction was stirred at rt until complete consumption of the startingmaterial indicated by TLC. The reaction was added water, 3% HCl untilpH<1 and extracted with EtOAc (×3). The organic phases were combined,washed with brine and dried over MgSO₄ before concentration to thecorresponding acetylene propanoic acid.

General Procedure III Wittig Reaction

A round bottomed flask was added aryl aldehyde (1 equiv), ethylbromoacetate (1.5 equiv), saturated aqueous NaHCO₃ (2 mL/mmol), EtOAc (1mL/mmol) and PPh₃ (1.4 equiv) and stirred vigorously at rt. Afterconsumption of the starting materials the reaction was added water andextracted with EtOAc (×3). The organic phases were combined, washed withbrine, dried over MgSO₄, concentrated under vacuum and purified by flashchromatography.

General Procedure IV Reduction

CoCl₂6H₂O (0.1 equiv) and aryl acrylate (1 equiv) was dissolved in MeOH(2 mL/mmol) under argon atmosphere. NaBH₄ (1.25-2 equiv) was added inportions of 25-50 mg when the colour faded from black-brown to pink.After consumption of the starting materials the reaction was added waterand extracted with EtOAc (×3). The organic phases were combined, washedwith brine, dried over MgSO₄, concentrated under vacuum and purified byflash chromatography.

Intermediate 1 (E)-Ethyl 3-(4-bromo-2-fluorophenyl)acrylate

A round bottomed flask was added 4-bromo-2-fluorobenzaldehyde (1005 mg,4.93 mmol), ethyl 2-bromoacetate (0.80 mL, 7.21 mmol), aqueous NaHCO₃and PPh₃ (1.81 g, 6.90 mmol) and stirred vigorously at rt. Afterconsumption of the starting materials the reaction was added water andextracted with EtOAc (×3). The organic phases were combined, washed withbrine, dried over MgSO₄, concentrated under vacuum and purified by flashchromatography (SiO₂, EtOAc:petroleum ether, 1:5) to give 1178 mg (87%)of a clear oil (white solid at 5° C.): R_(t)=13.67 min (HPLC); ¹H NMR(CDCl₃) δ 7.72 (d, J=16.2 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.34-7.27 (m,2H), 6.52 (d, J=16.2 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz,3H); ¹³C NMR (CDCl₃) δ 166.6, 160.9 (d, J=258.3 Hz), 136.0 (d, J=2.4Hz), 129.9 (d, J=3.7 Hz), 128.0 (d, J=3.7 Hz), 124.4 (d, J=9.9 Hz),121.7 (d, J=11.8 Hz), 121.5 (d, J=6.7 Hz), 119.9 (d, J=25.1 Hz), 60.8,14.3.

Intermediate 2 Ethyl 3-(4-bromo-2-fluorophenyl)propanoate

The title compound was prepared from (E)-ethyl3-(4-bromo-2-fluorophenyl)acrylate (1124 mg, 4.12 mmol) and NaBH₄ (277mg, 7.33 mmol) at 0° C. according to the general procedure IV to give979 mg (86%) of a clear oil after purification by flash chromatography(SiO₂, EtOAc:petroleum ether, 1:5): R_(t)=13.24 min (HPLC); ¹H NMR(CDCl₃) δ 7.22-7.17 (m, 2H), 7.10 (t, J=8.1 Hz, 1H), 4.12 (q, J=7.1 Hz,2H), 2.93 (t, J=7.6 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.23 (t, J=7.1 Hz,3H); ¹³C NMR (CDCl₃) δ 172.4, 161.0 (d, J=251.5 Hz), 131.8 (d, J=5.1Hz), 127.3 (d, J=3.0 Hz), 126.6 (d, J=16.2 Hz), 120.2 (d, J=9.1 Hz),119.0 (d, J=25.3 Hz), 60.6, 34.1 (d, J=1.0 Hz), 24.2 (d, J=2.0 Hz),14.2; ESI-MS m/z 297.0 (M+Na⁺).

Example 1 3-(2-Fluoro-4-(phenylethynyl)phenyl)propanoic acid

Ethyl 3-(2-fluoro-4-(phenylethynyl)phenyl)propanoate was prepared fromethyl 3-(4-bromo-2-fluorophenyl)propanoate (139 mg, 0.51 mmol) andphenylacetylene (0.07 mL, 0.64 mmol) according to the general procedureI to give 104 mg (69%) of an orange oily product after purification byflash chromatography (SiO₂, EtOAc:petroleum ether, 1:5): R_(f)=0.47(EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ 7.56-7.48 (m, 2H),7.39-7.31 (m, 3H), 7.25-7.15 (m, 3H), 4.13 (q, J=7.1 Hz, 2H), 2.98 (t,J=7.6 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H); ¹³C NMR(CDCl₃) δ 172.5, 160.7 (d, J=246.4 Hz), 131.7, 130.6 (d, J=6.1 Hz),128.5, 128.4, 128.1 (d, J=15.1 Hz), 127.5 (d, J=3.0 Hz), 123.2 (d,J=10.1 Hz), 122.9, 118.3 (d, J=24.2 Hz), 89.9, 88.1 (d, J=4.0 Hz), 60.6,34.2, 24.6 (d, J=2.0 Hz), 14.2; ESI-MS m/z 319.1 (M+Na⁺).

The title compound was prepared from ethyl3-(2-fluoro-4-(phenylethynyl)phenyl)propanoate (84 mg, 0.28 mmol)according to the general procedure II to give 63 mg (79%) of a paleyellow solid (purity 99.7% by HPLC) after purification by flashchromatography (SiO₂, EtOAc:petroleum ether, 1:2): R_(t)=12.49 min(HPLC); ¹H NMR (DMSO-d₆) δ 12.24 (s, 1H), 7.59-7.53 (m, 2H), 7.49-7.41(m, 3H), 7.40-7.30 (m, 3H), 2.87 (t, J=7.6 Hz, 2H), 2.56 (t, J=7.6 Hz,2H); ¹³C NMR (DMSO-d₆) δ 173.3, 160.0 (d, J=245.4 Hz), 131.3, 130.9 (d,J=5.1 Hz), 128.9, 128.7, 128.6, 127.5 (d, J=3.0 Hz), 121.9, 121.8 (d,J=10.1 Hz), 117.7 (d, J=24.2 Hz), 89.7, 88.0 (d, J=3.0 Hz), 33.3, 23.5;ESI-HRMS calcd for C₁₇H₁₃FO₂Na (M+Na⁺) 291.0793. found 291.0806.

Example 2 3-(2-Fluoro-4-(3-methylbut-3-en-1-yn-1-yl)phenyl)propanoicacid

Ethyl 3-(2-fluoro-4-(3-methylbut-3-en-1-yn-1-yl)phenyl)propanoate wasprepared from ethyl 3-(4-bromo-2-fluorophenyl)propanoate (127 mg, 0.50mmol) and 2-methylbut-1-en-3-yne (60 μL, 0.63 mmol) according to thegeneral procedure I to give 100 mg (77%) of a yellow oily product afterpurification by flash chromatography (SiO₂, EtOAc:petroleum ether, 1:9):R_(f)=0.52 (EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ 7.26-6.97 (m,3H), 5.35 (d, J=33.2 Hz, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.00-2.86 (m, 2H),2.67-2.57 (m, 2H), 1.97 (s, 3H), 1.23 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃)δ 172.5, 160.6 (d, J=247.0 Hz), 130.5 (d, J=6.1 Hz), 127.9 (d, J=16.2Hz), 127.5 (d, J=3.3 Hz), 126.6, 123.1 (d, J=9.1 Hz), 122.4, 118.2 (d,J=24.2 Hz), 91.1, 87.1 (d, J=3.2 Hz), 60.5, 34.2 (d, J=1.2 Hz), 24.6 (d,J=2.3 Hz), 23.4, 14.2.

The title compound was prepared from ethyl3-(2-fluoro-4-(3-methylbut-3-en-1-yn-1-yl)phenyl)propanoate (79 mg, 0.30mmol) according to the general procedure II to give 65 mg (92%) of apale yellow solid (purity 97.5% by HPLC): R_(t)=12.03 min (HPLC); ¹H NMR(CDCl₃) δ 11.24 (s, 1H), 7.28-6.98 (m, 3H), 5.35 (d, J=33.7 Hz, 2H),2.97 (t, J=7.5 Hz, 2H), 2.68 (t, J=6.9 Hz, 2H), 1.97 (s, 3H); ¹³C NMR(CDCl₃) δ 178.6, 160.6 (d, J=247.1 Hz), 130.5 (d, J=6.1 Hz), 127.5 (d,J=3.0 Hz), 127.5 (d, J=16.1 Hz), 126.6, 123.4 (d, J=10.1 Hz), 122.5,118.3 (d, J=24.2 Hz), 91.2, 87.0 (d, J=3.0 Hz), 33.9, 24.2 (d, J=2.0Hz), 23.4; ESI-HRMS calcd for C₁₄H₁₅FO₂ (M+H⁺) 233.0972. found 233.0963.

Intermediate 3 Methyl 3-(4-ethynyl-2-fluorophenyl)propanoate

Ethyl 3-(2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)propanoate wasprepared from ethyl 3-(4-bromo-2-fluorophenyl)propanoate (670 mg, 2.44mmol) and trimethylsilylacetylene (0.64 mL, 4.93 mmol) according to thegeneral procedure I. The crude product was dissolved in MeOH (25 mL),added potassium carbonate (683 mg, 4.94 mmol) and stirred vigorously for3 hours at room temperature. The reaction was added water and extractedwith EtOAc. The organic phases were combined, washed with brine, driedover MgSO₄, concentrated under vacuum and purified by flashchromatography (SiO₂, EtOAc:petroleum ether, 1:5) to give 375 mg (74%)of a yellow oil: R_(f): 0.49 (EtOAc:petroleum ether, 1:2): ¹H NMR(CDCl₃) δ 7.24-7.10 (m, 3H), 3.67 (s, 3H), 3.07 (s, 1H), 2.97 (t, J=7.7Hz, 2H), 2.63 (t, J=7.7 Hz, 2H); ¹³C NMR (CDCl₃) δ 172.9, 160.5 (d,J=247.5 Hz), 130.7 (d, J=6.1 Hz), 128.7 (d, J=16.2 Hz), 128.1 (d, J=4.0Hz), 122.0 (d, J=9.1 Hz), 118.9 (d, J=24.2 Hz), 82.3 (d, J=3.0 Hz),77.8, 51.7, 33.9 (d, J=1 Hz), 24.5 (d, J=3.0 Hz); ESI-MS m/z 229.1(M+Na⁺).

Example 3(Z)-3-(2-Fluoro-4-(3-methylpent-3-en-1-yn-1-yl)phenyl)propanoic acid

Methyl (Z)-3-(2-fluoro-4-(3-methylpent-3-en-1-yn-1-yl)phenyl)propanoatewas prepared from methyl 3-(4-ethynyl-2-fluorophenyl)propanoate (105 mg,0.51 mmol) and (Z)-2-bromobut-2-ene (60 μL, 0.59 mmol) according to thegeneral procedure I to give 60 mg (45%) of a pale yellow oily productafter purification by flash chromatography (SiO₂, EtOAc:petroleum ether,1:6): R_(f)=0.62 (EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ7.18-7.06 (m, 3H), 5.86-5.76 (m, 1H), 3.67 (s, 3H), 2.97 (t, J=7.6 Hz,2H), 2.63 (t, J=7.7 Hz, 2H), 1.96-1.90 (m, 3H), 1.90-1.84 (m, 3H); ¹³CNMR (CDCl₃) δ 173.0, 160.6 (d, J=246.9 Hz), 131.3, 130.5 (d, J=5.7 Hz),127.5 (d, J=16.1 Hz), 127.3 (d, J=3.2 Hz), 123.7 (d, J=9.9 Hz), 118.5,118.1 (d, J=23.6 Hz), 91.9 (d, J=3.1 Hz), 89.3, 51.7, 34.0 (d, J=1.3Hz), 24.6 (d, J=2.3 Hz), 22.8, 16.3; ESI-MS m/z 261.1 (M+H±).

The title compound was prepared from methyl(Z)-3-(2-fluoro-4-(3-methylpent-3-en-1-yn-1-yl)phenyl)propanoate (54 mg,0.21 mmol) according to the general procedure II to give 44 mg (86%) ofa pale yellow solid (purity 99.5% by HPLC): R_(t)=12.56 min (HPLC); ¹HNMR (CDCl₃) δ 7.18-7.08 (m, 3H), 5.86-5.77 (m, 1H), 2.97 (t, J=7.6 Hz,2H), 2.68 (t, J=7.7 Hz, 2H), 1.93-1.90 (m, 3H), 1.90-1.84 (m, 3H); ¹³CNMR (CDCl₃) δ 178.4, 160.6 (d, J=247.0 Hz), 133.4, 130.5 (d, J=5.8 Hz),127.4 (d, J=3.2 Hz), 127.2 (d, J=16.1 Hz), 123.8 (d, J=9.8 Hz), 118.5,118.2 (d, J=23.5 Hz), 91.8 (d, J=3.3 Hz), 89.4, 33.9, 24.2 (d, J=2.3Hz), 22.8, 16.4; ESI-HRMS calcd for C₁₅H₁₅FO₂Na (M+Na⁺) 269.0948. found269.0955.

Example 4(E)-3-(2-Fluoro-4-(3-methylpent-3-en-1-yn-1-yl)phenyl)propanoic acid

Methyl (E)-3-(2-fluoro-4-(3-methylpent-3-en-1-yn-1-yl)phenyl)propanoatewas prepared from methyl 3-(4-ethynyl-2-fluorophenyl)propanoate (105 mg,0.51 mmol) and (E)-2-bromobut-2-ene (60 μL, 0.59 mmol) according to thegeneral procedure I to give 85 mg (64%) of a pale yellow oily productafter purification by flash chromatography (SiO₂, EtOAc:petroleum ether,1:6): R_(f)=0.62 (EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ7.16-7.10 (m, 2H), 7.07 (d, J=10.9 Hz, 1H), 6.08-5.98 (m, 1H), 3.66 (s,3H), 2.95 (t, J=7.7 Hz, 2H), 2.62 (t, J=7.7 Hz, 2H), 1.86 (s, 3H), 1.74(d, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃) δ 173.0, 160.6 (d, J=246.4 Hz),133.4, 130.4 (d, J=5.7 Hz), 127.3 (d, J=16.1 Hz), 127.3 (d, J=3.2 Hz),123.8 (d, J=9.8 Hz), 118.3, 118.1 (d, J=23.6 Hz), 93.1, 84.5 (d, J=3.2Hz), 51.7, 34.0 (d, J=1.3 Hz), 24.5 (d, J=2.4 Hz), 16.8, 14.2.

The title compound was prepared from methyl(E)-3-(2-fluoro-4-(3-methylpent-3-en-1-yn-1-yl)phenyl)propanoate (78 mg,0.30 mmol) according to the general procedure II to give 68 mg (92%) ofa white solid (purity 99.4% by HPLC): R_(t)=12.53 min (HPLC); ¹H NMR(CDCl₃) δ 7.17-7.10 (m, 2H), 7.07 (d, J=11.1 Hz, 1H), 6.08-5.99 (m, 1H),2.96 (t, J=7.7 Hz, 2H), 2.67 (t, J=7.7 Hz, 2H), 1.86 (s, 3H), 1.74 (dd,J=7.1, 0.7 Hz, 3H); ¹³C NMR (CDCl₃) δ 178.5, 160.6 (d, J=246.9 Hz),133.5, 130.4 (d, J=5.6 Hz), 127.4 (d, J=3.2 Hz), 126.9 (d, J=16.1 Hz),123.9 (d, J=9.8 Hz), 118.3, 118.1 (d, J=23.6), 93.2, 84.5 (d, J=3.1 Hz),33.9 (d, J=1.0 Hz), 24.2 (d, J=2.4 Hz), 16.8, 14.2; ESI-HRMS calcd forC₁₅H₁₅FO₂Na (M+Na⁺) 269.0948. found 269.0961.

Example 5 3-(2-Fluoro-4-(o-tolylethynyl)phenyl)propanoic acid

Methyl 3-(2-fluoro-4-(o-tolylethynyl)phenyl)propanoate was prepared frommethyl 3-(4-ethynyl-2-fluorophenyl)propanoate (110 mg, 0.53 mmol) and1-bromo-2-methylbenzene (70 μL, 0.58 mmol) according to the generalprocedure I to give 82 mg (52%) of a pale yellow oily product afterpurification by flash chromatography (SiO₂, EtOAc:petroleum ether, 1:8):R_(f)=0.35 (EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ 7.47 (d, J=7.5Hz, 1H), 7.28-7.12 (m, 6H), 3.67 (s, 3H), 2.98 (t, J=7.6 Hz, 2H), 2.64(t, J=7.6 Hz, 2H), 2.49 (s, 3H); ¹³C NMR (CDCl₃) δ 172.9, 160.7 (d,J=247.1 Hz), 140.3, 131.9, 130.6 (d, J=6.1 Hz), 129.5, 128.6, 127.9 (d,J=16.2 Hz), 127.4 (d, J=3.0 Hz), 125.6, 123.5 (d, J=10.1 Hz), 122.7,118.2 (d, J=23.2 Hz), 92.1 (d, J=3.1 Hz), 88.9, 51.7, 34.0 (d, J=1.2Hz), 24.6 (d, J=2.3 Hz), 20.7; ESI-MS m/z 297.1 (M+H⁺).

The title compound was prepared from methyl3-(2-fluoro-4-(o-tolylethynyl)phenyl)propanoate (72 mg, 0.24 mmol)according to the general procedure II to give 65 mg (95%) of a whitesolid (purity 99.8% by HPLC): R_(t)=13.03 min (HPLC); ¹H NMR (CDCl₃) δ7.48 (d, J=7.5 Hz, 1H), 7.28-7.12 (m, 6H), 3.00 (t, J=7.5 Hz, 2H), 2.70(t, J=7.6 Hz, 2H), 2.50 (s, 3H); ¹³C NMR (CDCl₃) δ 178.5, 160.7 (d,J=247.3 Hz), 140.3, 131.9, 130.6 (d, J=6.1 Hz), 129.5, 128.6, 127.5 (d,J=16.1 Hz), 127.5 (d, J=3.2 Hz), 125.6, 123.6 (d, J=10.1 Hz), 122.6,118.2 (d, J=24.2 Hz), 92.0 (d, J=3.2 Hz), 89.0, 33.9, 24.3 (d, J=2.1Hz), 20.7; ESI-HRMS calcd for C₁₈H₁₆FO₂ (M+H⁺) 283.1129. found 283.1139.

Example 6 3-(4-((2-(Cyanomethyl)phenyl)ethynyl)-2-fluorophenyl)propanoicacid

Methyl 3-(4-((2-(cyanomethyl)phenyl)ethynyl)-2-fluorophenyl)propanoatewas prepared from methyl 3-(4-ethynyl-2-fluorophenyl)propanoate (105 mg,0.51 mmol) and 2-(2-iodophenyl)acetonitrile (149 mg, 0.61 mmol)according to the general procedure I to give 105 mg (64%) of pale yellowsolid after purification by flash chromatography (SiO₂, EtOAc:petroleumether, 1:5): R_(f)=0.29 (EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ7.53 (dd, J=24.1 Hz, 7.4 Hz, 2H), 7.43-7.31 (m, 2H), 7.30-7.17 (m, 3H),3.95 (s, 2H), 3.68 (s, 3H), 3.00 (t, J=7.6 Hz, 2H), 2.65 (t, J=7.6 Hz,2H); ¹³C NMR (CDCl₃) δ 172.9, 160.7 (d, J=248.5 Hz), 132.5, 131.8, 130.9(d, J=5.1 Hz), 129.3, 128.7 (d, J=16.2 Hz), 128.3, 128.3, 127.6 (d,J=3.0 Hz), 122.5, 122.4 (d, J=9.1 Hz), 118.3 (d, J=24.2 Hz), 117.3, 94.4(d, J=3.3 Hz), 86.5, 51.7, 33.9 (d, J=1.0 Hz), 24.6 (d, J=2.2 Hz), 22.8;ESI-MS m/z 344.1 (M+Na⁺).

The title compound was prepared from methyl3-(4-((2-(cyanomethyl)phenyl)ethynyl)-2-fluorophenyl)propanoate (73 mg,0.23 mmol) according to the general procedure II to give 48 mg (69%) ofa white solid (purity 98.7% by HPLC) after purification by flashchromatography (SiO₂, EtOAc[with 1% AcOH]:petroleum ether, 2:3):R_(t)=11.65 min (HPLC); ¹H NMR (Acetone-d₆) δ 7.60 (dd, J=17.5 Hz, 7.5Hz, 2H), 7.53-7.33 (m, 5H), 4.16 (s, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.67(t, J=7.6 Hz, 2H); ¹³C NMR (Acetone-d₆) δ 173.5, 161.5 (d, J=245.8 Hz),134.1, 133.2, 132.0 (d, J=6.1 Hz), 130.4, 130.1 (d, J=15.2 Hz), 129.6,129.1, 128.5 (d, J=3.0 Hz), 123.3 (d, J=9.9 Hz), 123.3, 118.8 (d, J=24.3Hz), 118.4, 94.8 (d, J=3.0 Hz), 87.4, 34.0, 24.8 (d, J=2.5 Hz), 22.9;ESI-HRMS calcd for C₁₉H₁₄FNO₂Na (M+Na⁺) 330.0901. found 330.0907.

Example 73-(4-((5-Cyano-2-methylphenyl)ethynyl)-2-fluorophenyl)propanoic acid

Methyl 3-(4-((5-cyano-2-methylphenyl)ethynyl)-2-fluorophenyl)propanoatewas prepared from methyl 3-(4-ethynyl-2-fluorophenyl)propanoate (110 mg,0.53 mmol) and 3-iodo-4-methylbenzonitrile (140 mg, 0.58 mmol) accordingto the general procedure I to give 115 mg (68%) of pale yellow oilyproduct after purification by flash chromatography (SiO₂,EtOAc:petroleum ether, 1:5): R_(f)=0.21 (EtOAc:petroleum ether, 1:2); ¹HNMR (CDCl₃) δ 7.75 (s, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz,1H), 7.25-7.17 (m, 3H), 3.68 (s, 3H), 3.00 (t, J=7.6 Hz, 2H), 2.65 (t,J=7.6 Hz, 2H), 2.56 (s, 3H); ¹³C NMR (CDCl₃) δ 172.8, 160.7 (d, J=247.7Hz), 145.6, 135.2, 131.5, 130.8 (d, J=5.7 Hz), 130.4, 128.8 (d, J=16.2Hz), 127.6 (d, J=4.0 Hz), 124.3, 122.4 (d, J=9.1 Hz), 118.3 (d, J=24.0Hz), 118.3, 110.1, 94.2 (d, J=3.1 Hz), 86.4, 51.7, 33.9 (d, J=1.1 Hz),24.6 (d, J=2.3 Hz), 21.2; ESI-MS m/z 344.1 (M+Na⁺).

The title compound was prepared from methyl3-(4-((5-cyano-2-methylphenyl)ethynyl)-2-fluorophenyl)propanoate (110mg, 0.34 mmol) according to the general procedure II to give 71 mg (68%)of a white solid (purity 99.3% by HPLC) after purification by flashchromatography (SiO₂, EtOAc[with 1% AcOH]:petroleum ether, 2:3):R_(t)=12.26 min (HPLC); ¹H NMR (Acetone-d₆) δ 7.88 (s, 1H), 7.69 (d,J=7.9 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.47-7.29 (m, 3H), 2.99 (t, J=7.6Hz, 2H), 2.66 (dd, J=14.8 Hz, 7.2 Hz, 2H), 2.59 (s, 3H); ¹³C NMR(Acetone-d₆) δ 173.5, 161.6 (d, J=245.4 Hz), 146.6, 135.8, 132.7, 132.1(d, J=5.7 Hz), 131.7, 130.3 (d, J=15.9 Hz), 128.5 (d, J=3.3 Hz), 125.0,123.1 (d, J=9.8 Hz), 118.9, 118.7, 111.0, 94.8 (d, J=3.1 Hz), 87.1,34.0, 24.8 (d, J=2.6 Hz), 21.1; ESI-HRMS calcd for C₁₉H₁₄FNO₂Na (M+Na⁺)330.0901. found 330.0892.

Intermediate 4 1-Bromo-2-((methylsulfonyl)methyl)benzene

2-Bromobenzylbromide (250 mg, 1.00 mmol), sodium methanesulfinate (303mg, 2.97 mmol) and DMF (2.5 mL) was added to a 10 mL cone shaped flaskand stirred at 60° C. for 1 hour. The reaction was cooled to roomtemperature, added water and extracted with EtOAc (×3). The organicphases were combined, washed with water (×2), brine (×1), dried overMgSO₄ and concentrated under vacuum to give 235 mg (94%) of a whitesolid: R_(f)=0.34 (EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ7.67-7.63 (m, 1H), 7.61 (dd, J=7.7 Hz, 1.5 Hz, 1H), 7.40 (td, J=7.6 Hz,0.9 Hz, 1H), 7.27 (td, J=7.8 Hz, 1.6 Hz, 1H), 4.52 (s, 2H), 2.82 (s,3H); ¹³C NMR (CDCl₃) δ 133.4, 133.1, 130.8, 128.5, 128.3, 125.0, 60.4,39.9; ESI-MS m/z 270.9 (M+Na⁺).

Example 83-(2-Fluoro-4-((2-((methylsulfonyl)methyl)phenyl)ethynyl)phenyl)propanoicacid

Methyl3-(2-fluoro-4-((2-((methylsulfonyl)methyl)phenyl)ethynyl)phenyl)propanoatewas prepared from methyl 3-(4-ethynyl-2-fluorophenyl)propanoate (104 mg,0.50 mmol) and 1-bromo-2-((methylsulfonyl)methyl)benzene (136 mg, 0.54mmol) according to the general procedure I to give 136 mg (72%) of apale yellow solid after purification by flash chromatography (SiO₂,EtOAc:petroleum ether, 1:2): R_(f)=0.12 (EtOAc:petroleum ether, 1:2); ¹HNMR (CDCl₃) δ 7.67-7.57 (m, 2H), 7.47-7.37 (m, 2H), 7.30-7.16 (m, 3H),4.57 (s, 2H), 3.69 (s, 3H), 3.01 (t, J=7.6 Hz, 2H), 2.80 (s, 3H), 2.66(t, J=7.6 Hz, 2H); ¹³C NMR (CDCl₃) δ 172.8, 160.7 (d, J=248.1 Hz), 133.3(d, J=32.7 Hz), 132.8, 131.5, 131.0 (d, J=5.7 Hz), 130.3, 129.5, 129.2,127.5 (d, J=3.3 Hz), 123.6, 122.0 (d, J=9.7 Hz), 118.3 (d, J=24.0 Hz),93.4 (d, J=3.2 Hz), 87.2, 59.5, 51.9, 39.4, 33.9 (d, J=1.2 Hz), 24.6 (d,J=2.3 Hz); ESI-MS m/z 375.1 (M+H±).

The title compound was prepared from methyl3-(2-fluoro-4-((2-((methylsulfonyl)-methyl)phenyl)ethynyl)phenyl)propanoate(109 mg, 0.29 mmol) according to the general procedure II to give 100 mg(95%) of a pale yellow solid (purity 99.6% by HPLC): R_(t)=10.71 min(HPLC); ¹H NMR (Acetone-d₆) δ 7.73-7.59 (m, 2H), 7.51-7.31 (m, 5H), 4.70(s, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.93 (s, 3H), 2.67 (t, J=7.6 Hz, 2H);¹³C NMR (Acetone-d₆) δ 173.5, 161.5 (d, J=245.8 Hz), 134.1 (d, J=6.2Hz), 133.3, 132.7, 132.0, 130.1 (d, J=16.0 Hz), 129.9, 129.7, 128.6 (d,J=3.0 Hz), 124.9, 123.3 (d, J=9.9 Hz), 118.8 (d, J=24.3 Hz), 93.5 (d,J=3.1 Hz), 88.4, 59.6, 40.5, 34.0, 24.8 (d, J=2.5 Hz); ESI-HRMS calcdfor C₁₉H₁₉O₄S (M+H⁺) 361.0467. found 361.0897.

Intermediate 5 1-Bromo-3-((methylsulfonyl)methyl)benzene

3-Bromobenzylbromide (260 mg, 1.04 mmol), sodium methanesulfinate (318mg, 3.12 mmol) and DMF (2.5 mL) was added to a 10 mL cone shaped flaskand stirred at 60° C. for 1 hour. The reaction was cooled to roomtemperature, added water and extracted with EtOAc (×3). The organicphases were combined, washed with water (×2), brine (×1), dried overMgSO₄ and concentrated under vacuum to give 252 mg (97%) of a whitesolid: R_(f)=0.15 (EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ7.60-7.52 (m, 2H), 7.37 (d, J=7.7 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 4.21(s, 2H), 2.80 (s, 3H); ¹³C NMR (CDCl₃) δ 133.4, 132.4, 130.6, 130.4,129.2, 123.1, 60.6, 39.4; ESI-MS m/z 270.9 (M+Na⁺).

Example 93-(2-Fluoro-4-((3-((methylsulfonyl)methyl)phenyl)ethynyl)phenyl)propanoicacid

Methyl3-(2-fluoro-4-((3-((methylsulfonyl)methyl)phenyl)ethynyl)phenyl)propanoatewas prepared from methyl 3-(4-ethynyl-2-fluorophenyl)propanoate (102 mg,0.50 mmol) and 1-bromo-3-((methylsulfonyl)methyl)benzene (138 mg, 0.55mmol) according to the general procedure I to give 116 mg (62%) of apale yellow solid after purification by flash chromatography (SiO₂,EtOAc:petroleum ether, 1:2): R_(f)=0.12 (EtOAc:petroleum ether, 1:2); ¹HNMR (CDCl₃) δ 7.59-7.52 (m, 2H), 7.41 (d, J=4.9 Hz, 2H), 7.32-7.15 (m,3H), 4.25 (s, 2H), 3.68 (s, 3H), 2.99 (t, J=7.7 Hz, 2H), 2.80 (s, 3H),2.65 (t, J=7.7 Hz, 2H); ¹³C NMR (CDCl₃) δ 172.9, 160.6 (d, J=247.3 Hz),133.5, 132.3, 130.7 (d, J=5.7 Hz), 130.5, 129.3, 128.7, 128.4 (d, J=16.0Hz), 127.6 (d, J=3.3 Hz), 124.0, 122.7 (d, J=9.7 Hz), 118.3 (d, J=23.9Hz), 89.2 (d, J=3.0 Hz), 88.8, 60.9, 51.7, 39.2, 33.9 (d, J=1.2 Hz),24.6 (d, J=2.3 Hz); ESI-MS m/z 375.1 (M+H⁺).

The title compound w as prepared from methyl3-(2-fluoro-4-((3-((methylsulfonyl)methyl)phenyl)ethynyl)phenyl)propanoate(90 mg, 0.24 mmol) according to the general procedure II to give 83 mg(96%) of a pale yellow solid (purity 99.7% by HPLC): R_(t)=10.56 min(HPLC); ¹H NMR (Acetone-d₆) δ 7.68 (s, 1H), 7.62-7.45 (m, 3H), 7.40 (t,J=7.9 Hz, 1H), 7.31 (dd, J=16.8 Hz, 9.4 Hz, 2H), 4.47 (s, 2H), 2.98 (t,J=7.6 Hz, 2H), 2.90 (s, 3H), 2.66 (t, J=7.6 Hz, 2H); ¹³C NMR(Acetone-d₆) δ 173.5, 161.5 (d, J=245.9 Hz), 134.7, 132.4, 132.2, 132.0(d, J=5.7 Hz), 131.1, 129.9 (d, J=16.0 Hz), 129.8, 128.5 (d, J=3.3 Hz),124.0, 123.5 (d, J=9.9 Hz), 118.7 (d, J=24.2 Hz), 89.9, 89.2 (d, J=3.2Hz), 60.4, 39.9, 34.0, 24.8 (d, J=2.5 Hz); ESI-HRMS calcd for C₁₉H₁₉O₄S(M+H⁺) 361.0467. found 361.0902.

Example 10 3-(2,6-Difluoro-4-(phenylethynyl)phenyl)propanoic acid

Ethyl (E)-3-(4-bromo-2,6-difluorophenyl)acrylate was prepared from4-bromo-2,6-difluorobenzaldehyde (1006 mg, 4.55 mmol) and ethyl2-bromoacetate (0.75 mL, 6.76 mmol) according to the general procedureIII to give 1274 mg (96%) of a yellow solid after purification by flashchromatography (SiO₂, EtOAc:petroleum ether, 1:4): R_(f)=0.60(EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ 7.68 (d, J=16.5 Hz, 1H),7.18-7.11 (m, 2H), 6.72 (d, J=16.5 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 1.34(t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃) δ 166.6, 161.3 (dd, J=260.1 Hz, 8.0Hz), 129.7, 124.9 (dd, J=8.7 Hz, 8.7 Hz), 123.4 (dd, J=13.1 Hz, 13.1Hz), 116.0 (dd, J=27.1 Hz, 2.7 Hz), 111.8 (dd, J=15.2 Hz, 15.2 Hz),60.8, 14.3; ESI-MS m/z 291.0 (M+H⁺).

Ethyl 3-(4-bromo-2,6-difluorophenyl)propanoate was prepared from(E)-ethyl 3-(4-bromo-2,6-difluorophenyl)acrylate (290 mg, 1.00 mmol) andNaBH₄ (102 mg, 2.70 mmol) at 0° C. according to the general procedure IVto give 202 mg (69%) of a clear oil after purification by flashchromatography (SiO₂, EtOAc:petroleum ether, 1:2): R_(t)=13.38 min(HPLC); ¹H NMR (CDCl₃) δ 7.09-7.01 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.95(t, J=7.8 Hz, 2H), 2.58 (t, J=7.8 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); ¹³CNMR (CDCl₃) δ 172.2, 161.3 (dd, J=251.5 Hz, 9.6 Hz), 127.9 (dd, J=10.1Hz, 10.1 Hz), 119.7 (dd, J=12.1 Hz, 12.1 Hz), 115.2 (d, J=29.8 Hz),61.6, 33.4, 17.9 (dd, J=2.5 Hz, 2.5 Hz), 14.1.

Ethyl 3-(2,6-difluoro-4-(phenylethynyl)phenyl)propanoate was preparedfrom ethyl 3-(4-bromo-2,6-difluorophenyl)propanoate (149 mg, 0.51 mmol)and phenylacetylene (0.07 mL, 0.64 mmol) according to the generalprocedure I to give 90 mg (56%) of a pale yellow solid afterpurification by flash chromatography (SiO₂, EtOAc:petroleum ether,1:10): R_(f)=0.55 (EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ7.56-7.46 (m, 2H), 7.41-7.31 (m, 3H), 7.07-6.98 (m, 2H), 4.14 (q, J=7.1Hz, 2H), 3.00 (t, J=7.8 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H), 1.24 (t, J=7.1Hz, 3H); ¹³C NMR (CDCl₃) δ 172.2, 161.1 (dd, J=248.4 Hz, 11.1 Hz),131.7, 128.8, 128.4, 123.3 (dd, J=12.1 Hz, 12.1 Hz), 122.5, 116.9 (dd,J=20.2 Hz, 20.2 Hz), 114.4 (dd, J=19.9 Hz, 8.2 Hz), 90.9, 87.2 (dd,J=4.0 Hz, 4.0 Hz), 61.6, 33.6, 18.1, 14.2; ESI-MS m/z 337.1 (M+Na⁺).

The title compound was prepared from ethyl3-(2,6-difluoro-4-(phenylethynyl)phenyl)propanoate (78 mg, 0.25 mmol)according to the general procedure II to give 69 mg (97%) of a whitesolid (purity 99.6% by HPLC): R_(t)=12.71 min (HPLC); ¹H NMR(Acetone-d₆) δ 7.62-7.52 (m, 2H), 7.49-7.38 (m, 3H), 7.22-7.12 (m, 2H),3.00 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H); ¹³C NMR (Acetone-d₆) δ173.2, 162.1 (dd, J=247.3 Hz, 10.1 Hz), 132.5, 129.9, 129.5, 124.1 (dd,J=12.6 Hz, 12.6 Hz), 123.3, 118.3 (dd, J=20.7 Hz, 20.7 Hz), 115.1 (dd,J=20.0 Hz, 8.5 Hz), 91.6, 87.7 (dd, J=3.7 Hz, 3.7 Hz), 33.5, 18.7 (dd,J=2.5 Hz, 2.5 Hz); ESI-HRMS calcd for C₁₇H₁₃F₂O₂ (M+H⁺) 287.0878. found287.0881.

Example 11 3-(3-Fluoro-4-(phenylethynyl)phenyl)propanoic acid

Ethyl (E)-3-(4-bromo-3-fluorophenyl)acrylate was prepared from4-bromo-3-fluorobenzaldehyde (500 mg, 2.46 mmol) and ethyl2-bromoacetate (0.40 mL, 3.61 mmol) according to the general procedureIII to give 650 mg (97%) of a pale yellow oily product (purity ˜90% by¹H NMR) after purification by flash chromatography (SiO₂,EtOAc:petroleum ether, 1:5): R_(f)=0.50 (EtOAc:petroleum ether, 1:2); ¹HNMR (CDCl₃) δ 7.57 (dd, J=15.3 Hz, 5.3 Hz, 2H), 7.27 (d, J=9.3 Hz, 1H),7.17 (d, J=8.3 Hz, 1H), 6.43 (d, J=16.0 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H),1.34 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃) δ 166.4, 159.3 (d, J=249.3 Hz),142.1 (d, J=3.0 Hz), 135.9 (d, J=7.1 Hz), 134.0, 124.8 (d, J=4.0 Hz),120.3, 115.2 (d, J=23.2 Hz), 111.0 (d, J=21.2 Hz), 60.8, 14.3; ESI-MSm/z 273.0 (M+H⁺).

Ethyl 3-(4-bromo-3-fluorophenyl)propanoate was prepared from (E)-ethyl3-(4-bromo-3-fluorophenyl)acrylate (310 mg, 1.14 mmol) and NaBH₄ (77 mg,2.04 mmol) at 0° C. according to the general procedure IV to give 270 mg(87%) of a clear oily product: R_(t)=12.98 min (HPLC); ¹H NMR (CDCl₃) δ7.44 (t, J=7.7 Hz, 1H), 6.98 (d, J=9.5 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H),4.13 (q, J=7.1 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H),1.23 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃) δ 172.3, 159.0 (d, J=248.5 Hz),142.4 (d, J=7.1 Hz), 133.4, 125.3 (d, J=4.0 Hz), 116.5 (d, J=22.2 Hz),106.5 (d, J=21.2 Hz), 60.6, 35.3, 30.2 (d, J=1.2 Hz), 14.2.

Ethyl 3-(3-fluoro-4-(phenylethynyl)phenyl)propanoate was prepared fromethyl 3-(4-bromo-3-fluorophenyl)propanoate (137 mg, 0.50 mmol) andphenylacetylene (0.07 mL, 0.64 mmol) according to the general procedureI to give 115 mg (78%) of a brown oil after purification by flashchromatography (SiO₂, EtOAc:petroleum ether, 1:8): R_(f)=0.60(EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ 7.58-7.50 (m, 2H), 7.42(t, J=7.7 Hz, 1H), 7.38-7.30 (m, 3H), 7.00-6.92 (m, 2H), 4.13 (q, J=7.1Hz, 2H), 2.95 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.24 (t, J=7.1Hz, 3H); ¹³C NMR (CDCl₃) δ 172.4, 162.6 (d, J=252.5 Hz), 143.5 (d, J=7.4Hz), 133.3 (d, J=1.5 Hz), 131.7, 128.5, 128.4, 124.0 (d, J=3.2 Hz),123.0, 115.5 (d, J=21.1 Hz), 109.7 (d, J=15.9 Hz), 94.0 (d, J=3.0 Hz),82.7, 60.6, 35.3, 30.7 (d, J=1.2 Hz), 14.2; ESI-MS m/z 261.1 (M+H⁺).

The title compound was prepared from ethyl3-(3-fluoro-4-(phenylethynyl)phenyl)propanoate (102 mg, 0.35 mmol)according to the general procedure II to give 85 mg (92%) of a paleyellow solid (purity 99.6% by HPLC): R_(t)=12.24 min (HPLC); ¹H NMR(Acetone-d₆) δ 7.61-7.47 (m, 3H), 7.47-7.39 (m, 3H), 7.22-7.13 (m, 2H),2.98 (t, J=7.5 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H); ¹³C NMR (Acetone-d₆) δ173.6, 163.2 (d, J=250.7 Hz), 145.9 (d, J=7.6 Hz), 134.1, 132.2, 129.6,129.5, 125.5 (d, J=3.0 Hz), 123.7, 116.4 (d, J=21.2 Hz), 110.0 (d,J=15.2 Hz), 94.5 (d, J=3.1 Hz), 83.3, 35.2, 31.2 (d, J=1.3 Hz); ESI-HRMScalcd for C₁₇H₁₄FO₂ (M+H⁺) 269.0972. found 269.0978.

Intermediate 6 (Z)-3-Methylpent-2-en-4-yn-1-ol

To a mixture of water (30 mL) and 3-methylpent-1-en-4-yn-3-ol (5.0 g, 52mmol) was added concentrated sulfuric acid (3.9 mL) and the reaction wasstirred at room temperature for 2 days. The reaction was quenched withsaturated NaHCO₃ solution and extracted with ether (3×). The organiclayer was washed with brine, dried with Na₂SO₄ and concentrated in vacuoto yield a crude green liquid. The crude product was distilled at 70° C.for 1 h to remove excess of ether and starting material. The oil bathtemperature was raised to 125° C. and vacuum was applied (10-15 mbar,vapour temperature—105° C.) which gave 2.81 g (56%) of a colorless oil(87% pure by HPLC with the E-isomer as major impurity): R_(t)=7.62 min;¹H NMR (CDCl₃) δ 5.96 (t, J=6.7 Hz, 1H), 4.34 (d, J=6.7 Hz, 2H), 3.18(s, 1H), 1.91 (s, 3H); ¹³C NMR (CDCl₃) δ 137.4, 119.9, 82.2, 81.8, 61.3,23.0.

Intermediate 7 (Z)-Ethyl3-(2-fluoro-4-(5-hydroxy-3-methylpent-3-en-1-yn-1-yl)phenyl)propanoate

A dried Schlenk flask charged with Na₂PdCl₄ (11 mg, 0.02 mmol),2-(di-tert-butylphosphino)-N-phenylindole (PIntB, 25 mg, 0.04 mmol), CuI(7.0 mg, 0.02 mmol), ethyl 3-(4-bromo-2-fluorophenyl)propanoate (0.5 g,1.82 mmol), TMEDA (3.3 mL) and water (0.36 mL), was evacuated andbackfilled with argon three times, then heated to 75° C.(Z)-3-Methylpent-2-en-4-yn-1-ol (280 mg, 2.91 mmol) was added to thereaction mixture and then heated at 75° C. for 30 min. The reactionmixture was cooled to ambient temperature, diluted with water andextracted with ethyl acetate. The organic phases were combined, washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography (SiO₂, EtOAc:petroleum ether, 3:7) togive 400 mg (75%) of a yellow oil (82% pure by HPLC with the E-isomer asmajor impurity): R_(t)=11.99 min; ¹H NMR (CDCl₃) δ 7.20-7.12 (m, 2H),7.09 (d, J=10.6 Hz, 1H), 5.94 (t, J=6.8 Hz, 1H), 4.40 (t, J=5.4 Hz, 2H),4.12 (q, J=7.1 Hz, 2H), 2.97 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H),1.97 (s, 3H), 1.50 (t, J=5.2 Hz, 1H), 1.23 (t, J=7.2 Hz, 3H); ¹³C NMR(CDCl₃) δ 172.6, 160.6 (d, J=246.2 Hz), 136.6, 130.7, 128.2, 128.1,127.4, 123.0, 122.9, 120.0, 118.1 (d, J=23.7 Hz), 93.0, 88.0, 61.3,60.6, 51.7, 34.2, 24.5, 23.0, 14.2.

Example 12(Z)-3-(2-Fluoro-4-(5-hydroxy-3-methylpent-3-en-1-yn-1-yl)phenyl)propanoicacid

The title compound was prepared from (Z)-ethyl3-(2-fluoro-4-(5-hydroxy-3-methylpent-3-en-1-yn-1-yl)phenyl)propanoate(54 mg, 0.19 mmol) according to the general procedure II to give 23 mg(47%) of a white solid (purity 99.9% by HPLC) after purification withpreparative HPLC: R_(t)=10.00 min; ¹H NMR (CDCl₃) δ 7.21-7.13 (m, 2H),7.10 (d, J=10.6 Hz, 1H), 5.95 (t, J=6.6 Hz, 1H), 4.40 (d, J=6.8 Hz, 2H),2.98 (t, J=7.6 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H), 1.97 (s, 3H); ¹³C NMR(CDCl₃) δ 177.1, 160.6 (d, J=246.5 Hz), 136.1, 130.6, 127.8 (d, J=15.9Hz), 127.5, 123.06 (d, J=9.8 Hz), 120.7, 118.2 (d, J=23.7 Hz), 93.0,87.9, 61.5, 33.6, 24.2, 23.1; ESI-HRMS calcd for C₁₅H₁₅FO₃Na (M+Na⁺)285.0897. found: 285.0896.

Example 13 3-(4-((3,5-Dichlorophenyl)ethynyl)-2-fluorophenyl)propanoicacid

Methyl 3-(4-((3,5-dichlorophenyl)ethynyl)-2-fluorophenyl)propanoate wasprepared from methyl 3-(4-ethynyl-2-fluorophenyl)propanoate (103 mg,0.50 mmol) and 1-bromo-3,5-dichlorobenzene (125 mg, 0.55 mmol) accordingto the general procedure I to give 128 mg (73%) of a pale yellow solidafter purification by flash chromatography (SiO₂, EtOAc:petroleum ether,1:5): R_(f)=0.49 (EtOAc:petroleum ether, 1:2); ¹H NMR (CDCl₃) δ 7.39 (d,J=1.9 Hz, 2H), 7.33 (t, J=1.9 Hz, 1H), 7.24-7.20 (m, 2H), 7.19-7.14 (m,1H), 3.68 (s, 3H), 2.99 (t, J=7.6 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H); ¹³CNMR (CDCl₃) δ 172.9, 160.6 (d, J=247.5 Hz), 135.0, 130.8 (d, J=5.7 Hz),129.8, 129.0, 128.8, 127.7 (d, J=3.3 Hz), 125.7, 122.1 (d, J=9.8 Hz),118.4 (d, J=24.1 Hz), 90.4 (d, J=3.0 Hz), 87.1, 51.7, 33.9 (d, J=1.0Hz), 24.6 (d, J=2.0 Hz).

The title compound was prepared from methyl3-(4-((3,5-dichlorophenyl)ethynyl)-2-fluorophenyl)propanoate (100 mg,0.29 mmol) according to the general procedure II to give 93 mg (96%) ofa white solid (purity 99.9% by HPLC): R_(t)=14.38 min (HPLC); ¹H NMR(DMSO-d₆) δ 12.25 (s, 1H), 7.73-7.68 (m, 1H), 7.67-7.60 (m, 2H),7.45-7.30 (m, 3H), 2.88 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H); ¹³CNMR (DMSO-d₆) δ 173.3, 160.0 (d, J=245.4 Hz), 134.4, 131.1 (d, J=5.1Hz), 129.8, 129.5 (d, J=16.0 Hz), 128.8, 127.8 (d, J=3.1 Hz), 125.2,121.0 (d, J=9.8 Hz), 118.0 (d, J=24.3 Hz), 90.6, 86.9, 33.3, 23.6 (d,J=2.0 Hz); ESI-HRMS calcd for C₁₇H₁₁Cl₂FO₂Na (M+Na⁺) 359.0012. found359.0007.

Example 143-(4-((2-(Difluoromethyl)-5-fluorophenyl)ethynyl)-2-fluorophenyl)propanoicacid

Methyl3-(4-((2-(difluoromethyl)-5-fluorophenyl)ethynyl)-2-fluorophenyl)propanoatewas prepared from methyl 3-(4-ethynyl-2-fluorophenyl)propanoate (99 mg,0.48 mmol) and 2-bromo-1-(difluoromethyl)-4-fluorobenzene (70 μL, 0.53mmol) according to the general procedure I to give 118 mg (70%) of apale yellow solid after purification by flash chromatography (SiO₂,EtOAc:petroleum ether, 1:5): R_(f)=0.47 (EtOAc:petroleum ether, 1:2); ¹HNMR (CDCl₃) δ 7.66 (dd, J=8.7 Hz, 5.6 Hz, 1H), 7.30-7.15 (m, 5H), 7.02(t, J=55.2 Hz, 1H), 3.68 (s, 3H), 3.00 (t, J=7.6 Hz, 2H), 2.65 (t, J=7.6Hz, 2H); ¹³C NMR (CDCl₃) δ 172.8, 163.4 (dt, J=252.2 Hz, 1.9 Hz), 160.7(d, J=247.9 Hz), 131.6 (dt, J=22.8 Hz, 3.3 Hz), 130.9 (d, J=5.7 Hz),129.2 (d, J=16.1 Hz), 127.7 (d, J=3.3 Hz), 127.7 (dt, J=10.9 Hz, 5.7Hz), 123.8 (dt, J=10.3 Hz, 6.1 Hz), 121.8 (d, J=9.7 Hz), 119.2 (d,J=23.6 Hz), 118.4 (d, J=24.1 Hz), 116.4 (d, J=22.0 Hz), 112.8 (t,J=238.8 Hz), 94.6 (d, J=3.1 Hz), 84.3-84.2 (m), 51.7, 33.9 (d, J=1.2Hz), 24.6 (d, J=2.3 Hz); ESI-MS m/z 373.1 (M+Na⁺).

The title compound was prepared from methyl3-(4-((2-(difluoromethyl)-5-fluorophenyl)ethynyl)-2-fluorophenyl)propanoate(75 mg, 0.21 mmol) according to the general procedure II to give 68 mg(95%) of a white solid (purity 98.8% by HPLC): t_(R)=12.53 min (HPLC);¹H NMR (Acetone-d₆) δ 7.78 (dd, J=8.7 Hz, 5.6 Hz, 1H), 7.50-7.32 (m,5H), 7.20 (t, J=54.9 Hz, 1H), 3.00 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz,2H); ¹³C NMR (Acetone-d₆) δ 173.5, 164.4 (dt, J=250.5 Hz, 1.9 Hz), 161.5(d, J=246.2 Hz), 132.7 (dt, J=22.7 Hz, 3.2 Hz), 132.1 (d, J=5.6 Hz),130.8 (d, J=16.0 Hz), 128.9 (dt, J=9.7 Hz, 5.9 Hz), 128.7 (d, J=3.3 Hz),124.6 (dt, J=10.4 Hz, 5.9 Hz), 122.6 (d, J=9.8 Hz), 120.0 (d, J=24.0Hz), 119.0 (d, J=24.4 Hz), 117.4 (d, J=22.3 Hz), 114.1 (t, J=237.0 Hz),95.3 (d, J=3.1 Hz), 94.9 (d, J=2.8 Hz), 34.0 (d, J=0.9 Hz), 24.8 (d,J=2.6 Hz); ESI-HRMS calcd for C₁₈H₁₂F₄O₂Na (M+Na⁺) 359.0666. found359.0680.

Biological Assays

The compounds were tested for their ability to mobilize calcium inGPR40-transfed cells as described by Christiansen et al. (J. Med. Chem.2011, 54, 6691-6703). Results for selected examples are given in Table1.

TABLE 1 GPR40 activity Example (pEC₅₀) 1 7.48 2 7.09 3 7.69 4 7.43 57.48 6 8.21 7 7.77 8 5.84 9 5.71 10 6.85 11 6.84 12 6.37 13 7.42 14 7.74Glucose Tolerance Test in Normal Mice

The study was conducted in accordance with UK Government Home Officeregulations, C57Bl/6 mice (6-7 weeks, Charles River) were given chowdiet (Bantin and Kingman, no 1 diet) and water ad lib. The mice wereunder controlled lighting conditions (lights on 8.00 h, 12 h light/12 hdark) and at a room temperature of 21°±1° C. The study was performedafter a few days rest to adapt to new environment and caging. Mice wererandomised to achieve similar mean body weight in each cage. 36 maleC57Bl/6 mice were grouped as follows:

A 2 groups of 3 mice control B 2 groups of 3 mice TUG 770 - 2 mg/kg p.o.C 2 groups of 3 mice TUG 770 - 10 mg/kg p.o. D 2 groups of 3 mice TUG770 - 50 mg/kg p.o. E 2 groups of 3 mice TUG 770 - 250 mg/kg p.o. F 2groups of 3 mice sitagliptin 10 mg/kg p.o.

Five hours prior to the start of the glucose tolerance test (07.00) foodwas removed and animals were given clean cages. Mice were treated withvehicle (10% (v/v) Cremophor, 10% DMSO, 80% of 5% mannitol in water) orcompound at 11.30 h and glucose at 12.00 h. Glucose was dissolved inwater (2 g/10 ml) and given to the mice i.p. with a load of 2 g/kg.Blood samples (20M were taken for the analysis of glucose concentrationsat −30, 0, 20, 40, 60, 90 and 120 minutes following glucoseadministration.

Blood Glucose Analysis

20 μl samples of blood were taken into disposable micro-pipettes (DadeDiagnostics Inc., Aguada, Puerto Rico) and glucose concentrationsdetermined after mixing with 0.38 ml of haemolysis reagent. Duplicate 20μl aliquots of this mixture was taken for each individual sample andplaced in a 96-well assay plate. To each well was added 180 μl aliquotsof glucose oxidase reagent (Thermo Trace, Victoria, Australia. Cat noTR5221), the samples were mixed and then left for approximately 30minutes. Samples were then analysed automatically using a SpectraMax-250and SoftMax Pro software (Molecular Devices Corporation, 1311 OrleansDrive, Sunnyvale, Calif. 94089, USA). The results were converted intoglucose concentration values using Prism software, version 3.0 (GraphPadSoftware Inc., San Diego, Calif., USA).

The plasma glucose concentrations of vehicle control, compound TUG-770(Example 6) in oral doses of 2, 10, 50 and 250 mg/kg and sitagliptin (10mg/kg p.o.) has been plotted against time in FIG. 1. The areas under thecurve (AUC) for each group are shown in FIG. 2.

The invention claimed is:
 1. A compound of the formula (I)

or a salt thereof wherein Ar is an optionally substituted monocyclic orfused aromatic or heteroaromatic ring system; n is an integer of 0-1; Xis —C(R⁴R⁵); m is an integer of 0-2; R¹, R⁴, and R⁶ are independentlyselected from the group consisting of hydrogen, optionally substituted(C₁-C₁₀)alkyl, optionally substituted (C₂-C₁₀)alkenyl, optionallysubstituted (C₂-C₁₀)alkynyl, optionally substituted (C₁-C₁₀)alkylene,optionally substituted (C₁-C₁₀)alkoxy, hydroxy, optionally substituted(C₂-C₁₀)dialkylamino, optionally substituted (C₁-C₁₀)alkylthio,optionally substituted (C₂-C₁₀)heteroalkyl, optionally substituted(C₂-C₁₀)heteroalkylene, optionally substituted (C₃-C₁₀)cycloalkyl,optionally substituted (C₃-C₁₀)heterocycloalkyl, optionally substituted(C₃-C₁₀)cycloalkylene, optionally substituted(C₃-C₁₀)heterocycloalkylene, halo, nitrile, (C₁-C₁₀)alkylsulfenyl,(C₁-C₁₀)alkylsulfinyl, optionally substituted (C₁-C₁₀)alkylsulfonyl,optionally substituted (C₁-C₁₀)haloalkyl, optionally substituted(C₁-C₁₀)perhaloalkyl, (C₂-C₁₀)-alkenyloxy, (C₃-C₁₀)-alkynyloxy, aryloxy,arylalkyloxy, heteroaryloxy, heteroarylalkyloxy,(C₁-C₆)alkyloxy-(C₁-C₄)alkyl optionally substituted aryl, optionallysubstituted heteroaryl, and optionally substituted arylalkyl; R² isselected from the group consisting of hydrogen, optionally substituted(C₁-C₁₀)alkyl, optionally substituted (C₂-C₁₀)alkenyl, optionallysubstituted (C₂-C₁₀)alkynyl, optionally substituted (C₁-C₁₀)alkylene,optionally substituted (C₂-C₁₀)heteroalkyl, optionally substituted(C₂-C₁₀)heteroalkenyl, optionally substituted (C₂-C₁₀)heteroalkylene,optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted(C₃-C₁₀)cycloalkenyl, optionally substituted (C₃-C₁₀)cycloalkylene,optionally substituted (C₃-C₁₀)heterocycloalkyl, optionally substituted(C₃-C₁₀)heterocycloalkenyl, optionally substituted(C₃-C₁₀)heterocycloalkylene, optionally substituted (C₁-C₁₀)haloalkyl,optionally substituted (C₁-C₁₀)haloalkenyl, optionally substituted(C₁-C₁₀)haloalkylene, optionally substituted (C₁-C₁₀)perhaloalkyl,optionally substituted (C₁-C₁₀)perhaloalkenyl, optionally substituted(C₁-C₁₀)perhaloalkylene, and optionally substituted arylalkyl; Ar and R²may be further substituted by R⁶; R³ is selected from hydrogen andhalogen; R⁵ is selected from hydrogen and optionally substituted(C₁-C₃)alkyl; wherein substituted means one or more substituentsselected from: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′,—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″,—NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′,—SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl, —(C₂-C₅)alkenyl, and—NO₂, said R′, R″ and R″ each independently refer to hydrogen,unsubstituted (C₁-C₆)alkyl and (C₂-C₆)heteroalkyl, unsubstituted aryl,aryl substituted with one to three halogens, unsubstituted(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy or (C₁-C₄)-thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups, provided that when R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6- or 7-membered ring; with the proviso thatthe following compound is excluded from protection:(S)-2-tert-butoxycarbonylamino-3-(4-{(R)-4-[1-(5-chloropyrimidin-2-yl)-piperidin-4-yl]pent-1-ynyl}-2-fluorophenyl)propionicacid.
 2. The compound of claim 1 or a salt thereof, wherein R¹, R⁴ andR⁶ are independently selected from hydrogen and (C₁-C₃)alkyl.
 3. Thecompound of claim 1 or a salt thereof, wherein R¹ is hydrogen.
 4. Thecompound of claim 1 or a salt thereof, wherein R⁴ and R⁵ are hydrogen.5. The compound of claim 1 or a salt thereof, wherein R³ is hydrogen. 6.The compound of claim 1 or a salt thereof, wherein n is 1 and Ar isselected from the group consisting of an optionally substituted phenyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 4-thiazolyl, 2-furyl, 3-furyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrrazolyl,2-pyrrazolyl, 3-pyrrazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl,4-triazolyl, 5-tetrazolyl, 2-naphthyl, 3-naphthyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl,2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,7-benzothiazolyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl,6-indolyl and 7-indolyl.
 7. The compound of claim 1 or a salt thereof,wherein n is 1 and Ar is phenyl.
 8. The compound of claim 1 or a saltthereof, wherein n is 1 and Ar is 4-pyridyl.
 9. The compound of claim 7or a salt thereof, with R² substituted in the ortho or meta positionrelative to the alkyne of formula (I).
 10. The compound of claim 9 or asalt thereof, wherein R² is selected from hydrogen and (C₁-C₆)alkyl. 11.The compound of claim 1 or a salt thereof, wherein R¹ is methyl, R⁴ andR⁵ are hydrogen, and R¹ is connected to X with a covalent bond.
 12. Thecompound of claim 1 or a salt thereof, wherein n is 0 and R² is selectedfrom (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₂-C₁₀)heteroalkyl,(C₂-C₁₀)heteroalkenyl, (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkenyl,(C₅-C₁₀)bicycloalkyl, (C₅-C₁₀)heterobicycloalkyl and(C₃-C₁₀)heterocycloalkenyl.
 13. The compound of claim 12 or a saltthereof, wherein R² is selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)heteroalkyl, (C₂-C₆)heteroalkenyl, (C₃-C₆)cycloalkyl and(C₃-C₆)cycloalkenyl.
 14. The compound of claim 12 or a salt thereof,wherein R² is vinyl substituted by 1-3 (C₁-C₃)alkyls.
 15. The compoundof claim 1 or a salt thereof, wherein n is 0 and R² is(C₄-C₆)cycloalken-1-yl substituted by 1-3 R⁶ groups.
 16. A process forthe preparation of a compound of claim 1 or a salt thereof, comprisingany combination of three or more steps from the alternative pathways:

wherein R7 is selected from hydrogen and (C₁-C₁₀)alkyl, and Y isselected from halogen and triflate.